tbuckley/cabot-search huggingface dataset:
The effect of statin use on survival outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with androgen receptor targeted therapies (ART).
Authors: George Slade Mellgard, Nathaniel Saffran, Zakaria Chakrani, Stephen Mccroskery, Nicole Taylor, Bobby Chi-Hung Liaw, Matt D. Galsky, Kai Tsao, Vaibhav G. Patel
Journal: Journal of Clinical Oncology (2023)

194 Background: Statins may reinforce and provide a compounded effect on ART by decreasing cholesterol levels thus decreasing de novo androgen synthesis. We aim to investigate the clinical effect of concurrent statin and ART use on outcomes of mCRPC patients. Methods: We conducted a retrospective analysis on mCRPC patients receiving ART from a single institution. Relevant demographic and clinical data was collected in addition to ART treatment course, statin treatment, and survival outcomes. Our primary outcome was PSA progression free survival (PFS) and our secondary outcomes were overall survival (OS) and associated prognostic factors for both PSA PFS and OS. Chi-squared test and Wilcoxon signed ranked test were used to compare baseline characteristics, and a Cox proportional hazards regression model was used to estimate hazard ratios (HR) with 95% confidence interval (CI) for overall survival (OS) and PSA PFS. Results: 153 patients were included in the analysis between 2010 and 2021. 67 patients (mean age 73.8 years) received concurrent statins and 86 patients (mean age 67.6 years) did not. Median PSA PFS was 37.4 months for patients that received concurrent statins and 17.4 months for patients that did not receive statins. On univariate and multivariate analyses, there was no statistically significance difference between groups for PSA PFS (HR 0.7; CI 0.44-1.1; p=0.122). Median OS was 35.6 months for patients that received concurrent statins and 24.0 months for patients who did not. There was no statistical significance between groups for OS on univariate or multivariate analyses (HR 0.67; CI 0.42-1.06; p=0.087). Conclusions: Although results were not statistically significant, our study illustrates that concurrent statin use exhibits improved time to PSA progression and OS in mCRPC patients. Larger multi-center and further prospective studies are warranted to elucidate the relationship between statin use and overall outcomes in this population.
A living interactive systematic review and network meta-analysis evaluating systemic therapies in metastatic castration-sensitive prostate cancer (mCSPC).
Authors: Irbaz Bin Riaz, Syed Arsalan Ahmed Naqvi, Huan He, Rabbia Siddiqi, Noureen Asghar, Praful Ravi, Syed A. Hussain, Parminder Singh, Alan Haruo Bryce
Journal: Journal of Clinical Oncology (2023)

193 Background: We maintain a network meta-analysis for the treatment of mCSPC using a living interactive evidence (LIvE) synthesis framework. Recently, the STAMPEDE trial presented evidence regarding a new triplet regimen (enzalutamide-abiraterone-androgen deprivation therapy [E+AAP+ADT]). Hence, in this report we provide the most-up-to-date evidence to inform the choice of optimal therapy in mCSPC patients. Methods: Phase III randomized controlled trials (RCTs) assessing treatment intensification with androgen pathway inhibitors (API), docetaxel (D), or both in patients with mCSPC were included. Mixed treatment comparisons for overall-survival (OS) and progression-free survival (PFS) were made across randomized comparisons using a frequentist network-meta-analysis. Additionally, subgroup data from three trials (ENZAMET, TITAN, ARCHES) by the receipt of docetaxel were abstracted to evaluate the comparative effectiveness of different triplet regimens. Treatment effects were expressed as hazard ratio (HR) and 95% confidence intervals (CI). Relative treatment rankings were evaluated using P-scores and assessed in congruency with the pairwise estimates. Results: This report includes 10 clinical trials (30 references) and over 11500 patients updated as of 1 st October 2022. Using randomized data in overall patient population, AAP+D+ADT (rank 1; HR: 0.50; 95% CI: 0.35-0.72) and E+AAP+ADT (rank 4; HR: 0.76; 0.62-0.93) significantly improved PFS compared to D+ADT (rank 7) but not when compared to E+ADT (rank 2) and APA+ADT (rank 3). Similarly, darolutamide (DARO)+D+ADT (rank 1; HR: 0.68; 0.57-0.81), AAP+D+ADT (rank 2; HR: 0.75; 0.59-0.95) significantly improved OS when compared to D+ADT (rank 7). Efficacy by volume of disease and timing of metastatic presentation was consistent with prior update. Using subgroup data by the receipt of docetaxel, a total of five triplet regimens (DARO+D+ADT, AAP+D+ADT, E+D+ADT, apalutamide (APA)+D+ADT, and E+AAP+ADT) were evaluable for comparisons. E+D+ADT (rank 3) improved PFS compared to D+ADT (rank 9; HR: 0.52; 0.41-0.66) and E+AAP+ADT (rank 6; HR: 0.70; 0.52-0.94). Compared to AAP+ADT (rank 7), E+D+ADT (HR: 0.64; 0.49-0.84) and AAP+D+ADT (rank 2; 0.62; 0.42-0.91) significant improved PFS. However, no significant differences were observed among E+D+ADT, AAP+D+ADT, and APA+D+ADT. Similarly, DARO+D+ADT (rank 1) improved OS compared to APA+D+ADT (HR: 0.47; 0.24-0.93). Conclusions: Current evidence favors the use of emerging triplet regimens over docetaxel doublet but not API doublets in overall population. Among different triplets, E+AAP+ADT may not delay progression compared to docetaxel triplets. Hence, access to treatment, toxicity, disease volume and timing of metastases should be carefully considered in mCSPC patients.
The landscape of prostate cancer research in Canada.
Authors: Mike Fraser, Atiqa Mohammad
Journal: Journal of Clinical Oncology (2023)

394 Background: Prostate cancer (PCa) is the most prevalent malignancy in Canadian men; in 2023, an estimated 24,700 men will be diagnosed while ~4,700 will die of their disease. Lifetime risk of developing PCa is approximately 1-in-8 and approximately 3% of all deaths of Canadian men are caused by the disease. While Canada has a robust, modern health research landscape, with major academic centres located in all provinces and territories, the investment in academic PCa research – and the impact of that investment – has not been systematically quantified. An improved understanding of this landscape is necessary to ensure research funding remains efficient, impactful, and equitable. As such, we evaluated the size, scope, and impact of the investment in academic PCa research in Canada. Methods: We extracted funding records from the Canadian Research Information System (CRIS), the United States Congressionally Directed Medical Research Program database and the United States National Institutes of Health RePORT database for the National Cancer Institute, using keywords ‘prostate’ OR ‘prostatic’ AND ‘cancer’ OR ‘carcinoma’ for 1999-2021. US-sourced records were included when the principal investigator (PI) was based at a Canadian institution at the time the award was granted. Records were validated using data from the Canadian Cancer Research Alliance (CCRA). Intramural and industry-derived funding was unavailable and thus excluded from the analysis. Results: We identified 1,748 unique funding events (FEs) from 33 sources. These FEs involved 1,561 investigators and had an inflation-adjusted value of $682,113,116. The top three funders of PCa research were the Canadian Institutes of Health Research, Movember Canada, and the Canadian Cancer Society. Basic and translational research received ~83% of all funding while psychosocial, health economics, and epidemiology research received only ~7.2%. Strikingly, we found that 30.5% of all funding was held by 1% of investigators. We identified 6,671 dyads ( ie. pairs of collaborating investigators); 85% collaborated only once, while 15% collaborated at least twice (range: 2-19). Female investigators participated in significantly fewer collaborations than males (P: 3.28 x 10 -3 ) and were less likely than expected to serve as PI (P: 8.87 x 10 -8 ). FEs with ≥ one female PI had a significantly lower value than those with only male PIs (P: 1.34 x 10 -6 ) and FEs with only female PIs had a significantly value than those with only male PIs (P: 7.32 x 10 -4 ). Conclusions: While Canadian PCa research has been highly funded over the past 25 years, there remain substantial funding disparities across scientific disciplines, geographic regions, and, in particular, gender. There is also substantial ‘wealth inequality’; a small minority of investigators receive most of the funding. We are currently assessing stakeholder attitudes toward these disparities, to help inform the next phase of PCa research funding in Canada.
Transdermal square-wave testosterone therapy: A pilot trial in metastatic castration-resistant prostate cancer.
Authors: Nellowe Candelario, Andrew Nicklawsky, Laura Graham, Elaine T. Lam, Eryn Callihan, Michael Wacker, Thomas W. Flaig, Elizabeth R Kessler
Journal: Journal of Clinical Oncology (2023)

188 Background: Metastatic castration-resistant prostate cancer (mCRPC) becomes resistant to anti-androgen therapies due to a variety of adaptive mechanisms. Intramuscular bipolar androgen therapy (BAT) which alternates between high and low testosterone (T) levels is therapeutically active in mCRPC and confers sensitivity to second-generation androgen receptor antagonists such as enzalutamide (ENZA). We hypothesized that transdermal T with sustained supraphysiologic T levels would lead to high response rates to ENZA in mCRPC. We also hypothesized Square-wave transdermal T therapy would be a safe alternative to BAT due to the ability to quickly withdraw therapy in the setting of symptoms. Methods: This was an open-label, single-site, phase 2 feasibility trial in men with asymptomatic mCRPC who had not previously received ENZA. Transdermal T was administered at a dose of 100 mg/day for a minimum of 12 weeks and until disease progression. Therapy was then switched to ENZA 160 mg/day until next disease progression. Patients who initially responded to T could receive a second course of transdermal T followed by ENZA, remaining on study until progression on both T and ENZA, or for the 12-month study duration, whichever was sooner. ADT was continued throughout. The primary endpoint of the study was feasibility. T dose was adjusted to achieve T levels between 900-1500 ng/dL. Secondary end points included PSA50 response rate (50% decline in PSA) and safety. Results: Fifteen patients were enrolled. Ten (66.7%) had Gleason &gt;8 disease. Thirteen (86.7%) patients had bone metastases. Median baseline PSA was 11.73 ng/mL. Primary endpoint of feasibility based on patient recruitment and retention was met. The median testosterone level on T was 901.3 ng/dL (Range: 645.2 to 1171.1). Median time on therapy was 15.9 weeks on T and 25.9 weeks on ENZA. PSA50 was 13.3% on initial T therapy and 66.7% after switching to ENZA. Three (20%) patients did not initiate ENZA after T progression. Two desired to avoid androgen-related side effects and 1 initiated chemotherapy. No Grade 3 or higher adverse events (AEs) occurred on T and the most common AEs were weight gain, rash, and nipple sensitivity. Conclusions: Square-wave transdermal T alternating with ENZA is feasible and achieves adequate T levels in the treatment of asymptomatic mCRPC. Given the acceptable safety profile and quick reversibility, transdermal T warrants further exploration, and we have expanded enrollment to include higher risk patient populations. Clinical trial information: NCT03734653 .
A multi-center, open-label, randomized dose expansion study of PF-06821497, a potent and selective inhibitor of enhancer of zeste homolog 2 (EZH2), in patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Mariona Calvo, Konstantin Penkov, Alexander I. Spira, Irene Moreno Candilejo, Neal D. Shore, Tian Zhang, Begoña Mellado-Gonzalez, Teresa Alonso Gordoa, Luis Paz-Ares Rodriguez, Stefano R. Tarantolo, Juan José Soto, Robert S. Alter, Claudia Andreu-Vieyra, Timothy Bowler, Arnab K Maity, Subramanian Hariharan, Michael Thomas Schweizer
Journal: Journal of Clinical Oncology (2023)

TPS282 Background: Enhancer of zeste homolog 2 (EZH2) encodes the histone methyltransferase component of the polycomb repressive complex-2, inducing transcriptional silencing of target genes, and is altered in cancers such as follicular lymphoma (FL), small cell lung cancer (SCLC), and metastatic castration-resistant prostate cancer (mCRPC). We evaluated the pharmacokinetics (PK), safety, and antitumor activity of PF-06821497, a potent and selective inhibitor of EZH2, in an ongoing phase I trial (NCT03460977 ) in patients (pts) with SCLC, CRPC, and FL as monotherapy and in combination with standard of care therapies. For pts with CRPC, the PF-06821497 recommended dose for expansion (RDE) is 1250 mg BID, in combination with enzalutamide plus androgen deprivation therapy (E). Part 2B of this trial further explores outcomes for pts dosed with PF-06821497 and E compared with E monotherapy. Methods: Part 2B compares the safety and efficacy of twice-daily PF-06821497 in combination with E (160 mg daily) (treatment arm) versus E monotherapy (control arm) administered continuously in patients with mCRPC previously treated with abiraterone. At trial entry, all pts will have evidence of prostate cancer progression per the modified Prostate Cancer Working Group 3 Criteria. Prior treatment with E is not allowed. Approximately 80 participants will be randomized in a 1:1 fashion into two arms, in US, Spain, and other countries. Approximately 40 participants are required in each arm to have 80% power in the study in order to detect a hazard ratio of 0.5 (E plus PF-06821497: E alone). Patients randomized to E alone have the option to add PF-06821497 to their regimen upon confirmed radiographic disease progression. The primary objectives are to confirm the safety and tolerability of PF-06821497 in combination with E in pts with mCRPC, and to assess the effect of PF-06821497 in combination with E versus E monotherapy on radiographic progression free survival. Secondary objectives include further evaluation of anti-tumor activity of PF-06821497, and assessment of single and multiple dose PK when given in combination with E. The impact of PF-06821497 in combination with E and of E alone in men with mCRPC on patient reported outcomes will also be assessed. Clinical trial information: NCT03460977 .
P-MCP treatment in non-metastatic biochemically relapsed prostate cancer (BRPC-M0): Final long-term results of a prospective phase II study.
Authors: Daniel Keizman, Moshe A. Frenkel, Avivit Peer, Igal Kushnir, Eli Rosenbaum, David Leonid Sarid, Ilan Leibovitch, Roy Mano, Ofer Yossepowitch, David Margel, Ido Wolf, Ravit Geva, Keren Rouvinov, Hadas Dresler, Isaac Eliaz
Journal: Journal of Clinical Oncology (2023)

162 Background: 30% of patients with localized PC will have a biochemical relapse post local therapy. Their optimal treatment remains elusive. While androgen deprivation therapy is effective in reducing PSA level, its long-term benefit remains undefined, and it is toxic. Thus, evaluation of new nontoxic compounds in these patients is warranted. PectaSol-C modified citrus pectin (P-MCP) is an inhibitor of galectin-3 protein, which is involved in prostate cancer pathogenesis. We herein report the final long-term results of a multi-center phase 2 study of P-MCP treatment in BRPC-M0. Methods: Patients with BRPC-M0 were enrolled and treated with P-MCP, 4.8 grams X 3/day, for 6 months (first phase of trial). Patients without PSA progression and/or with improvement of PSA doubling time (PSADT), and with negative scans, were treated for an additional 12 months (second phase of trial). Results: 59 patients were initially enrolled. After initial 6 months of therapy, 46 patients (78%) without disease progression entered the second phase of additional 12 months therapy. Among them, 7 patients withdrew consent and chose to continue therapy out of pocket. Of the remaining 39 patients, after another year of therapy (total of 18 months), 85% (n=33) had an overall long-term response, with a decreased/stable PSA (62 %, n=24), and improvement of PSADT (90 %, n=35), and with negative scans. No patient had grade 3/4 toxicity. Conclusions: P-MCP may have a durable long-term efficacy in patients with BRPC-M0. Clinical trial information: NCT01681823 .
A phase 1/2 study of REGN4336, a PSMAxCD3 bispecific antibody, alone and in combination with cemiplimab in patients with metastatic castration-resistant prostate cancer.
Authors: William Kevin Kelly, Arif Hussain, Biren Saraiya, Pradeep Thanigaimani, Furong Sun, Frank A. Seebach, Israel Lowy, Sabina Sandigursky, Elizabeth Miller
Journal: Journal of Clinical Oncology (2023)

TPS284 Background: Prostate cancer is the leading cause of new cancer diagnoses and the second most common cause of cancer-related death in American men. Prognosis is especially poor for men with metastatic castration resistant prostate cancer (mCRPC). Prostate-specific membrane antigen (PSMA) is highly expressed on malignant prostate tissue but shows limited expression on normal tissue. As such, PSMA is an excellent research target for treatment of mCRPC. REGN4336 is a PSMAxCD3 bispecific antibody designed to facilitate T-cell–mediated killing of PSMA-expressing tumor cells. In preclinical models, REGN4336 demonstrated strong PSMA-dependent antitumor activity that was dose-dependent. Preclinical data also support clinical research into the combination of REGN4336 with cemiplimab (anti–programmed cell death-1) for treating mCRPC. Methods: This is an open-label, Phase 1/2, first-in-human, multicenter dose-escalation study with dose expansion evaluating safety, tolerability, pharmacokinetics (PK), and antitumor activity of REGN4336 administered subcutaneously alone and in combination with intravenous cemiplimab in patients with mCRPC (NCT05125016). Patients must have received at least two prior lines of systemic therapy approved for metastatic and/or castration-resistant disease including a second-generation anti-androgen therapy. In Module 1, REGN4336 as monotherapy is administered weekly but may be extended to once every 3 weeks following identification of the minimal pharmacologically active dose. In Module 2, REGN4336 will be administered in combination with cemiplimab (350 mg) once every 3 weeks after a 4-week REGN4336 monotherapy lead-in cycle. Study therapies are administered until disease progression, intolerable adverse events, withdrawal of consent, or a study withdrawal criterion is met. The primary objectives in dose escalation are to evaluate the safety, tolerability, PK, and recommended phase 2 dosing regimen (RP2DR) of REGN4336 alone and in-combination with cemiplimab. Expansion cohort(s) will be enrolled once RP2DRs have been determined. During the expansion phase, the primary objective is to assess clinical activity, as measured by objective response rate with REGN4336 alone or in combination with cemiplimab per modified Prostate Cancer Working Group 3 criteria. At selected sites, PSMA positron emission tomography/computed tomography scans will be performed at predefined timepoints on study. This study is currently open to enrollment. Clinical trial information: NCT03088540 .
Survival outcomes of metastatic castration-resistant prostate cancer in Brazil (LACOG 1818).
Authors: Fernando Cotait Maluf, Suelen P. S. Martins, Deusdedit Cortêz Vieira Silva Neto, Gustavo Werutsky, Jose Augusto Rinck Jr, Diogo Assed Bastos, Roberto Odebrecht Rocha, Andre P. Fay, Roni de Carvalho Fernandes, Daniel da Motta Girardi, Daniel Vilarim Araujo, Augusto C. A. Mota, Aline Bobato Lara Gongora, Bruno Melo Fernandes, Ana Caroline Fonseca Alves, Cristina de Deus Anjos Tavares Sampaio, Andréa Lopes Ponte de Souza, Rafaela Gomes de Jesus, Gustavo Cartaxo de Lima Gössling, Andrey Soares
Journal: Journal of Clinical Oncology (2023)

TPS272 Background: Treatment of metastatic castration-resistant prostate cancer (mCRPC) has been steadily evolving during the last decade, but access remains a significant issue in low- and middle-income countries (LMICs). As novel therapies emerge and translate into clinical practice, the gap in treatment patterns between patients who do or do not have access to these therapies is expected to increase. The resulting disparities in outcomes are likely to be more noticeable in countries with pronounced inequality, such as Brazil. In Brazil, while a minority of patients have private insurance and have access to nearly all available treatment options, approximately 75% of patients depend on the public health system, which is unable to afford most of the recent treatment innovations for mCRPC, such as novel hormonal agents (NHA) or PARP inhibitors. LACOG 1818 was developed to investigate and compare outcomes of patients with mCRPC treated at private and public hospitals in Brazil. Methods: LACOG 1818 (NCT04962919) is a retrospective multicentric study investigating disparities in cancer treatment and survival among public and private institutions in Brazil. Patients with mCRPC diagnosed within January 2014 and December 2017 will be included and their data will be abstracted from medical records. Primary endpoint is cause-specific survival, comparing patients from private and public institutions. We estimate that 299 events are needed to detect a hazard ratio of 0.75 indicating a lower risk of prostate cancer-related death for patients treated at private institutions with a power of 80% and a bicaudate significance level of 10%. Considering a follow up of 24 months and a median cause-specific survival of 20 months in patients from public institutions, 590 patients are planned to be included. Secondary endpoints include describing comorbidities, sociodemographic and clinicopathological characteristics of patients with mCRPC; comparing overall survival of patients with mCRPC treated at public and private institutions; comparing treatments patterns of patients with mCRPC treated at public and private institutions; and describing skeleton-related complications, bone-directed treatments, and admission rates. From January 2020 to August 2022, 244 of planned 590 patients have been enrolled in 7 Brazilian centers. Additional 12 centers are still planned to open before 2023. Results are expected in the first semester of 2023. Clinical trial information: NCT04962919 .